doi:10.1093/brain/awl123
Brain (2006), 129, 2288–2296
Clinical findings and diagnostic tests in the
MV2 subtype of sporadic CJD
Anna Krasnianski,1 Walter J. Schulz-Schaeffer,2 Kai Kallenberg,3 Bettina Meissner,1
Donald A. Collie,5 Sigrun Roeber,4 Mario Bartl,1 Uta Heinemann,1 Daniela Varges,1
Hans A. Kretzschmar4 and Inga Zerr1
Departments of 1Neurology, 2Neuropathology and 3Neuroradiology, Georg-August University Göttingen,
4
Department of Neuropathology, Ludwig-Maximillian University Munich, Germany and 5Department of Neuroradiology,
Western General Hospital Edinburgh, UK
Corresponding author: Prof. Dr Inga Zerr, Neurologische Klinik und Poliklinik, Georg-August-Universität Göttingen,
Robert-Koch Strasse 40, D-37075 Göttingen, Germany
E-mail: [email protected]
Atypical clinical course and low sensitivity of established diagnostic tests are the main diagnostic problems in
the MV2 subtype of sporadic Creutzfeldt–Jakob disease (sCJD). Clinical symptoms and signs, MRI, EEG and
biochemical CSF markers were studied in 26 patients. Histological findings were semiquantitatively evaluated.
Compared with typical sCJD, the disease duration was prolonged (median 12 months). Dementia, ataxia and
psychiatric symptoms were present in all patients. Extrapyramidal signs were observed in 88%. T2-weighted
MRI showed basal ganglia hyperintensities in 90%. Increased thalamic signal intensity was detected in 88% on
diffusion-weighted MRI. Increased CSF tau-protein was found in 83%, and the 14-3-3 test was positive in 76%.
The EEG revealed periodic sharp wave complexes in only two patients. Kuru plaques, severe thalamic and basal
ganglia gliosis and spongiform changes, and neuronal loss in the pulvinar were the prominent histological
features. At least one of the three diagnostic tests (MRI, tau- and 14-3-3 protein) supported the clinical diagnosis
in all patients. MRI was the most sensitive of the diagnostic tests applied. Thalamic hyperintensities were
observed unusually frequently. Prolonged disease duration, early and prominent psychiatric symptoms,
absence of typical EEG, thalamic hyperintensities on MRI and relatively low 14-3-3 protein sensitivity may
be suspicious for variant CJD. However, distinct sensory symptoms and young age at onset, which are often
found in the latter, are not common in the MV2 subtype, and the pulvinar sign was observed in only one case.
Keywords: CJD; MV2 subtype; MRI; Pulvinar sign; diagnosis
Abbreviations: sCJD = sporadic Creutzfeldt–Jakob disease
Received November 25, 2005. Revised January 25, 2006. Accepted April 10, 2006. Advance Access publication May 23, 2006
Introduction
Sporadic Creutzfeldt–Jakob disease (sCJD) is a rare transmissible disease characterized by accumulation of pathological prion protein (PrPSc) in the CNS. The polymorphism at
codon 129 of the prion protein gene (PRNP) and the prion
protein types 1 and 2 are the basis for a molecular classification of sCJD (Parchi et al., 1996, 1999). An alternative classification of sCJD included the polymorphism at codon 129
and three main prion protein types (Collinge et al., 1996; Hill
et al., 2003).
The most common MM1/MV1 sCJD subtype is found
in 75% of sCJD cases (Parchi et al., 1999). According to
them the MV2 subtype comprises 9% of sCJD cases. Ataxia,
dementia, the lack of PSWCs and prolonged disease duration
were reported as typical in the MV2 subtype. Kuru plaques
were the most characteristic histological finding. However,
neither MRI nor biochemical CSF analysis was performed in
that study. In other studies on a limited number of MV2
patients, a low sensitivity of the 14-3-3 protein test was
reported (Zerr et al., 2000b; Castellani et al., 2004).
Atypical clinical course and low sensitivity of established
diagnostic tests have been reported to be the main problems
for diagnosing the MV2 subtype. The aim of the present
study is to improve the diagnosis of patients with this
sCJD subtype. We performed a detailed analysis of clinical
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The MV2 subtype of sCJD
features, EEG and MRI in 26 patients with the MV2-type
sCJD. Biochemical CSF markers such as tau-protein, neuronspecific enolase (NSE), S-100B and Ab-peptide 1-42 were
investigated in addition to 14-3-3 proteins.
Patients and methods
Study design
German patients with suspected CJD were reported to the CJD
Surveillance Unit in Göttingen and Munich and examined on
site. CSF, blood samples and copies of the important diagnostic
tests (MRI, EEG, laboratory tests) were taken. The patients were
classified according to established diagnostic criteria (WHO, 1998,
2001; Zerr et al., 2000a).
MRI and EEG findings
The MR images from MV2 patients and, additionally, from control
patients with the MM1 subtype were reviewed by two neuroradiologists (K.K. and D.C.) who were aware of the clinical diagnosis, but
not of the CJD type (sporadic, familial, iatrogenic, variant CJD),
codon 129 genotype, PrPSc type or clinical features. Seven cortical
regions, the basal ganglia and cerebellum were analysed semiquantitatively for hyperintensities in each available imaging. The EEGs
were analysed according to established criteria (Steinhoff et al.,
1996).
Neuropathological and molecular studies
From 1993 to 2004, 582 neuropathologically confirmed sCJD cases
were identified in Germany. The PrPSc type was determined in 221
of them according to Parchi et al. (1996). Western blot analysis,
immunohistochemistry and the analysis of PRNP were performed
by standard methods (Kitamoto et al., 1992; Kretzschmar et al.,
1996; Schulz-Schaeffer et al., 2000). No PRNP mutations were
detected. Semiquantitative evaluation of spongiosis, neuronal loss
and gliosis was performed as described previously (Parchi et al.,
1999). Eleven brain regions (superior frontal, cingulated, inferior
temporal and inferior parietal gyrus; visual cortex; head of the
caudate nucleus; middle part of the putamen; the pulvinar and
dorsomedial thalamic nucleus; CA1 region of hippocampus; and
vermis of the cerebellum) were investigated.
Biochemical CSF analysis
The 14-3-3 protein analysis was performed at least twice in each
CSF sample as described previously (Zerr et al., 1998). Tau-protein
was measured by Innotest hTau ELISA, and Ab-peptide 1-42 by
Innotest b-Amyloid 1-42 ELISA (Innogenetics N.V., Ghent, Belgium). NSE and S-100B were quantified by a commercially available
immunoluminometric assay (Liaison NSE and Liaison Sangtec 100,
DiaSorin S.p.A. Saluggia, Italy).
Statistical analysis
Significances (P) were tested by the Sigmastat 3.1 software (Systat
Software Inc., Point Richmond, USA) using the Student’s t-test/
Mann–Whitney rank sum test or chi-square test/Fisher exact test.
Correlations (r) were tested by the Sigmastat 3.1 software using
Pearson test. A P-value <0.05 was considered as statistically
significant.
Brain (2006), 129, 2288–2296
2289
Results
Study collective
The MV heterozygosity at codon 129 of the PRNP and the
PrPSc type 2 were found in 26 patients (12% of 221 patients
investigated; 15 female, 11 male). The median age at onset was
64 years (range 53–75); the median disease duration was 12
months (range 4–27).
Clinical findings
The data on the clinical symptoms and signs including the
time of onset are shown in Tables 1, 2 and 3. Dementia
(n = 10) and ataxia (n = 9) were the most common initial
symptoms. Two patients presented with blurred vision; two
with extrapyramidal tremor; and one each with paraesthesia,
unspecified anxiety and nervousness. Dementia, ataxia and
psychiatric symptoms were present in all patients, and extrapyramidal signs were observed in 88% during the disease
course. In 18% the disease remained monosymptomatic for
longer than 6 months. CJD was not suspected initially in any
patient (Table 4), but for the first time 8 months after disease
onset (mean).
Magnetic resonance imaging
MR images were available in 20 patients. The investigation
was performed in the median 8 months after symptom onset
(range 1–18 months). The semiquantitative evaluation of the
MRI findings is shown in Table 5. Basal ganglia hyperintensities on T2-weighted MRI were found in 90% of the
patients. The highest sensitivity for cortical hyperintensities
was observed in the DWI (88%) with the frontal cortex as the
most commonly affected region (63%). Hyperintensities in
the pulvinar (Fig. 1) were found in 5 of 20 patients (25%) on
T2-weighted MRI and in 7 of 8 patients with available DW
(88%). However, the classical pulvinar sign according to
revised criteria was seen in only one patient on FLAIR
and DWI imaging (Fig. 2) (Collie et al., 2001). The occurrence of thalamic hyperintensities showed no significant correlation with disease duration or time at which the MRI was
performed.
Surprisingly high frequency of thalamic hyperintensities in
our MV2 patients led us to compare their MRI findings with
those of 17 German CJD study MM1 patients presenting the
Table 1 Main symptoms and signs—time of onset
(months) in 26 patients
Symptom/sign
Median
Mean 6 SD
Dementia
Ataxia
Extrapyramidal
Myoclonus
Visual/oculomotor
Pyramidal
Akinetic mutism
1
1
6
7.5
7.5
8
9.5
1.9
2.1
6.3
8.4
6.8
7.4
9.0
6
6
6
6
6
6
6
2.6
3.1
4.2
4.2
4.5
3.4
2.9
Range
0–11
0–11
0–15
3–17
0–12
3–13
5–12
2290
Brain (2006), 129, 2288–2296
A. Krasnianski et al.
Table 2 Clinical symptoms and signs during disease
course in 26 patients
Table 3 Psychiatric and neuropsychological symptoms
and signs in 26 patients during disease course
Symptoms and signs
n (%)
Symptoms and signs
n (%)
Dementia
Ataxia
Extrapyramidal
Rigidity*
Tremor
Involuntary movements
Akinesia
Myoclonus
Visual/oculomotor
Gaze palsy
Saccadic pursuit
Nystagmus
Diplopia
Blurred vision
Metamorphopsia
Hemianopsia
Pyramidal
Akinetic mutism
Vegetative
Loss of weight
Hyperhidrosis
Obstipation
Other
Primitive reflexes
Dysarthria
Sleep disturbance
Dizziness
Dysphagia
Vigilance disorder
Sensory
Epileptic seizures
Headache
Weight gain
26
26
23
19
9
6
3
18
12
3
3
2
1
1
1
1
9
4
9
8
4
1
(100)
(100)
(88)
(73)
(34)
(23)
(11.5)
(69)
(47)
(11.5)
(11.5)
(8)
(4)
(4)
(4)
(4)
(34)
(15)
(34)
(31)
(15)
(4)
Psychiatric
Hallucinations*
Restlessness
Depression
Fear
Aggressiveness
Paranoia
Euphoria
Neuropsychological
Disorder of frontal brain
Apraxia
Aphasia
Acalculia
Agraphia
Spatial agnosia
26
13
11
10
10
9
7
3
17
17
12
9
2
2
1
17
15
14
10
7
6
5
3
3
1
(65)
(58)
(54)
(38)
(27)
(23)
(18)
(12)
(12)
(4)
*Rigidity was considered as present if the tone increase was
waxy or a cogwheel phenomenon was found.
classical sCJD subtype (17 T2-, 10 FLAIR-, 6 DWI- and
4 PD-weighted MRI). Basal ganglia hyperintensities were
found in 83% of DWI-, 70% of FLAIR-, 50% of PD- and
41% of T2-weighted MRI. No thalamic hyperintensities were
detected in the MM1 patients.
EEG
The data on at least two EEGs (range 2–6; median 4 months)
were available in all patients. The first EEG was obtained
4.5 months (median; range 0.5–15 months) and the last EEG
10 months (range 2.5–19 months) after disease onset.
PSWCs were found in only two patients 4 months and
11.5 months after onset (sensitivity 8%).
CSF
A lumbar puncture (LP) was performed in 25 patients (once
in 20, twice in 3, three times in 2 patients). Data on
(100)
(50)
(42)
(38)
(38)
(34)
(27)
(11.5)
(65)
(65)
(47)
(34)
(8)
(8)
(4)
*Visual hallucinations in all patients with hallucinations; acoustic
hallucinations in four of these patients.
Table 4 Initial diagnosis in 26 patients
Diagnosis
n
Multiple system atrophy
Alzheimer’s disease
Unclassified dementia
Dementia and ataxia
Depression
Psycho-organic syndrome
Hysterical neurosis
Somatization
Pick’s disease
Dementia and polyneuropathy
Tremor and polyneuropathy
Unclear ataxia
Delirium
Unclear dementia and cervical myelopathy
5
4
3
3
2
1
1
1
1
1
1
1
1
1
Table 5 Signal hyperintensities on MRI in 20 patients
T2
(n = 20)
FLAIR
(n = 10)
PD
(n = 7)
Cortical
4 (20%) 8 (80%) 3 (43%)
Frontal
2 (10%) 4 (40%) 2 (29%)
Cingulate gyrus
2 (10%) 5 (50%) 3 (43%)
Parietal
3 (15%) 4 (40%) 2 (29%)
Occipital
2 (10%) 6 (60%) 2 (29%)
Hippocampus
–
–
1 (5%)
Temporal
3 (15%) 4 (40%) 2 (29%)
Insula
–
–
–
Basal ganglia
18 (90%) 10 (100%) 7 (100%)
Nucleus caudatus 18 (90%) 10 (100%) 7 (100%)
Putamen
17 (85%) 9 (90%) 6 (86%)
Pallidum
2 (10%) 1 (10%) –
Pulvinar thalami
5 (25%) 7 (70%) 4 (57%)
Cerebellum
–
–
–
DWI
(n = 8)
7
5
3
3
4
1
3
2
8
8
6
–
7
–
(88%)
(63%)
(38%)
(38%)
(50%)
(13%)
(38%)
(25%)
(100%)
(100%)
(75%)
(88%)
The MV2 subtype of sCJD
Brain (2006), 129, 2288–2296
sensitivity of the biochemical markers and repeated LPs are
shown in Table 6. Repetitive LPs led to detection of 14-3-3
proteins in two of three initially negative patients. The interval between the repeated LPs varied from 21 days to 9
months (median 3 months). The positive 14-3-3 test was
obtained 8 months and the negative one 6 months after
the disease onset (medians). The time at which the LP
was performed was not significantly different in the two
groups. The tau-protein was the most sensitive CSF marker
(83%). The simultaneous tau- and 14-3-3 protein investigation showed the highest sensitivity (89%).
About 25% of our MV2 patients could be classified either
as possible sCJD or as possible vCJD and one patient as
probable vCJD or probable sCJD according to WHO criteria
(WHO, 1998, 2001; Will et al., 2000).
2291
prominent histological finding except for the pulvinar and
the vermis, where gliosis was the most distinct feature. The
caudate nucleus showed the most pronounced spongiform
changes, whereas gliosis and neuronal loss were especially
prominent in the pulvinar. Nerve cell loss correlated significantly with disease duration in four cortical regions and in
the pulvinar (r = 0.607; P = 0.0045 for temporal, r = 0.499;
P = 0.0251 for occipital, r = 0.576; P = 0.0098 for parietal,
A
Histological findings
Semiquantitative analysis of gliosis, spongiform changes and
neuronal loss was performed in 11 brain regions in
20 patients (Table 7). Spongiform changes were the most
B
Fig. 1 Axial PD-weighted MRI showing hockey stick-like thalamic
Fig. 2 (A) Axial FLAIR-weighted and (B) diffusion-weighted
MRI showing the pulvinar sign.
hyperintensities. The pulvinar signal is not more intense than
in other subcortical nuclei.
Table 6 Biochemical CSF markers in MV2 patients
CSF marker
Range
Median
1. LP
Sensitivity 1. LP (%)
2. LP
3. LP
Cumulative sensitivity (%)
14-3-3 protein
Tau (cut-off >1300 pg/ml)
Aß 1-42 (cut-off <450 pg/ml)
S-100 B (cut-off >4.2 ng/ml)
NSE (cut-off >25 ng/ml)
–
316–13 153 pg/ml
120–682 pg/ml
0.9–20.4 ng/ml
2–95 ng/ml
–
2610 pg/ml
366 pg/ml
4.9 ng/ml
30 ng/ml
17/25
17/24
14/23
15/24
13/24
68
71
61
63
54
3/5
3/5
4/4
4/4
3/5
1/2
1/2
0/1
1/1
2/2
76
83
70
67
63
1. LP = first lumbar puncture; 2. LP = second lumbar puncture; 3. LP = third lumbar puncture. Number of patients with
positive test as numerator; number of patients investigated as denominator.
2292
Brain (2006), 129, 2288–2296
r = 0.722; P = 0.0003 for frontal cortex; r = 0.569; P = 0.03 for
the pulvinar). Gliosis correlated significantly with disease
duration in three cortical regions (r = 0.524; P = 0.0177
for temporal, r = 0.531; P = 0.0192 for parietal, r = 0.575;
P = 0.0079 for frontal cortex). Spongiform changes correlated significantly with disease duration only in the frontal
cortex (r = 0.609; P = 0.0043). No significant difference was
found in the severity of histological changes in the pulvinar
in patients with or without the positive pulvinar sign on
MRI. In the cerebellum, kuru plaques were seen in all
patients.
Discussion
In the present study, the sequential cases from systemic
surveillance with consistent data collection in one country
were analysed. Similar to the study of Parchi et al. (1999),
which reported the MV2 subtype in 9% of investigated sCJD
cases, we found this subtype in 12% of German sCJD
patients. Since kuru plaques were found in all our MV2
patients (Parchi et al., 1996), the MV2 subtype corresponds
to the 3MV subtype of the classification of Collinge et al.
(1996; Hill et al., 2003). The PrPSc typing was carried out
in all patients in whom frozen brain tissue was available
independently from clinical features or other peculiarities
of the concrete cases. However, we cannot completely
exclude the possibility that some abnormal phenotypes
such as cases with very long disease duration were not
referred to the Surveillance Unit by external physicians
because of a clinical misdiagnosis.
In line with the earlier study, dementia and ataxia were
present in all patients and also the most frequent initial
clinical symptoms (Parchi et al., 1999). The cortical visual
disturbances previously not reported in the MV2 subtype
were found in two of our patients as an initial symptom
and in one patient during the later disease course (Parchi
et al., 1999).
All our MV2 patients developed psychiatric symptoms
during the disease course. The prevalence of psychiatric
symptoms in our patients was clearly higher than that
reported previously both for the MV2 subtype and typical
sCJD, but very similar to that in variant CJD (vCJD)
(Lundberg, 1998; Parchi et al., 1999; Will et al., 2000). In
contrast to vCJD, only few MV2 patients initially presented
with psychiatric symptoms (Will et al., 2000). However, in
18% of our patients a psychiatric or psychosomatic disease
was the first diagnosis suspected. The high prevalence of
psychiatric symptoms may be explained by the slow disease
progression, which enabled the patients to report their psychiatric problems.
The frequency of extrapyramidal signs in the present study
was higher than in MV2 patients and unselected sCJD
reported previously (Parchi et al., 1999; Zerr and Poser,
2002). In contrast, lower prevalence of pyramidal signs
was found (Parchi et al., 1999; Zerr and Poser, 2002). Similar
to the findings in a larger sCJD patient group, 18% of our
A. Krasnianski et al.
patients developed sensory symptoms (Meissner et al., 2004).
This was much higher than in the earlier study on the MV2
subtype, but clearly lower than in vCJD (Parchi et al., 1996;
Collie et al., 2001).
Myoclonus is a characteristic sign, which often leads to
the suspicion of sCJD for the first time. In line with a previous study, myoclonus occurred in our patients as late as
7.5 months (median) after disease onset and was less frequent than reported for all sCJD patients (Parchi et al., 1999;
Zerr and Poser, 2002).
In order to ensure a degree of consistency in clinical
assessments we compared the clinical features in our MV2
patients with those in other sCJD subtypes included in the
German CJD Surveillance Study (Table 8). While dementia
was present in almost all patients in each subtype investigated, ataxia was significantly more frequent than in MV1,
MM2 and VV1 patients. Myoclonus in our MV2 cases was
significantly more rare than in MM1 cases. Pyramidal signs
were less frequent than in other sCJD subtypes. Extrapyramidal signs were significantly more common than in the
VV1 and VV2 subtypes. Frequency of visual symptoms in
our MV2 patients was not significantly different from that in
other subtypes.
Summarizing, frequency of some neurological and psychiatric abnormalities revealed in our patients was higher
than that reported previously. We cannot entirely exclude
that it might be due to a more detailed clinical assessment in
our study. However, some symptoms and signs such as the
cortical visual impairment not previously reported in the
MV2 subtype were very distinct. The relatively high number
of patients with the MV2 subtype in the present study may
be a possible cause for these discrepancies.
In contrast to the previous studies involving smaller numbers of MV2 patients, which reported a 14-3-3 protein sensitivity of 30 and 57%, we found a higher sensitivity of 76%.
This was still lower than in typical sCJD (Zerr et al., 2000b;
Zerr and Poser, 2002; Castellani et al., 2004). Repetitive LPs
led to detection of 14-3-3 proteins in two of the three initially
negative patients. Thus, repetitive LPs can help to support the
diagnosis in the MV2 subtype. The negative LP results were
obtained not significantly earlier than the positive, and one of
the three patients remained 14-3-3 protein negative in spite
of repeated punctures. It may be presumed that the stage of
disease when the LP was performed is not the only cause for
lower 14-3-3 protein sensitivity in the MV2 subtype. No
obvious correlation between severity of histological changes
and 14-3-3 test sensitivity was found (Castellani et al., 2004).
Longer disease duration and slow disease progression were
proposed as possible causes, but high 14-3-3 test sensitivity
was also reported in a larger group of younger non-MV2
sCJD patients with prolonged disease course (Castellani
et al., 2004; Boesenberg et al., 2005).
Interestingly, the sensitivity of tau-protein was the highest
among all CSF markers evaluated, but still lower than
in a previous study on unselected sCJD patients (Otto
et al., 1997). The simultaneous tau- and 14-3-3 protein
2.3 6 0.7
3.2 6 0.5
1.9 6 0.6
2.5 6 0.7
3.4 6 0.5
1.8 6 0.6
2.2 6 0.7
2.7 6 0.7
2.4 6 0.7
2.8 6 0.6
2.6 6 0.7
2.3 6 0.7
3.0 6 0.5
2.6 6 0.9
2.6 6 0.6
2.2 6 0.6
3.1 6 0.5
2.2 6 0.6
Cingulate
gyrus
(n = 20)
2.2 6 0.7
2.6 6 0.9
2.2 6 0.8
Parietal
(n = 19)
1.9 6 0.6
2.1 6 0.8
1.9 6 0.6
Occipital
(n = 20)
2.3 6 0.8
2.7 6 1.0
2.2 6 0.8
Temporal
(n = 20)
64
67
61
67
67
44
(53–75)
(31–86)
(53–79)
(60–82)
(55–81)
(19–55)
–
n.s.1
n.s.1
n.s.1
n.s.1
P < 0.0012
Age at onset (years)*
12
4
5
14
7
21
(4–27)
(1–38)
(2–20)
(3–24)
(2–14)
(10–49)
–
P < 0.0012
P<0.0012
n.s.1
P < 0.0012
P = 0.0072
Disease
duration (months)*
100
99
100
100
96
100
–
n.s.3
n.s.4
n.s.4
n.s.4
n.s.4
Dementia
100
90
67
67
100
56
Ataxia
–
n.s.3
P = 0.0074
P = 0.0074
n.s.4
P = 0.0024
69
94
92
92
63
56
–
P = 0.0023
n.s.4
n.s.4
n.s.4
n.s.4
Myoclonus
34
78
67
83
44
78
–
P < 0.0013
n.s.4
P = 0.0134
n.s.4
P = 0.054
Pyramidal
88
81
92
92
52
67
–
n.s.3
n.s.4
n.s.4
P = 0.0064
P = 0.0034
Extrapyramidal
1.3 6 0.9
2.2 6 1.2
0.8 6 0.8
CA1
region
(n = 20)
Hippocampus
Krasnianski et al. (2006); bMeissner et al. (2005); P, statistical significance of frequency of each clinical feature compared with that in the MV2 subtype: 1Student t-test;
2
Mann–Whitney rank sum test; 3chi-square test; 4Fisher exact test; n.s., not significant; *as median and range.
26
83
12
12
27
9
MV2
MM1
MV1
MM2a
VV2
VV1b
a
n
sCJD
subtype
Table 8 Frequency of the main symptoms (%) during disease course in different sCJD suptypes (German CJD Surveillance Study)
Results as mean 6 SD. 0, no changes; 1, mild changes; 2, moderate changes; 3, severe changes; 4, maximal changes.
Gliosis
Spongiosis
Neuronal loss
Frontal
(n = 20)
Putamen
(n = 19)
Mediodorsal
nucleus
(n = 16)
Pulvinar
(n = 14)
Caudate
nucleus
(n = 19)
Cortex
Basal ganglia
Thalamus
Table 7 Semiquantitative analysis of neuropathological changes in MV2 patients
47
63
25
33
59
22
–
n.s.3
n.s.4
n.s.4
n.s.4
n.s.4
Visual/
oculomotor
2.2 6 0.9
1.5 6 0.8
1.4 6 0.6
Vermis
(n = 20)
Cerebellum
The MV2 subtype of sCJD
Brain (2006), 129, 2288–2296
2293
2294
Brain (2006), 129, 2288–2296
A. Krasnianski et al.
Table 9 Sensitivity of diagnostic tests in different sCJD suptypes (German CJD Surveillance Study)
sCJD subtype
EEG (%)
MV2
MM1
MV1
MM2a
VV2
VV1b
2/26 (8)
65/78 (83)
7/11 (64)
5/12 (42)
1/21 (5)
0/9 (0)
a
MRI (BG) (%)
–
P < 0.0012
P < 0.0011
P = 0.0221
n.s.1
n.s1
18/20 (90)
36/71 (51)
5/7 (71)
2/8 (25)
15/22 (68)
2/7 (29)
14-3-3 (%)
–
P = 0.0021
n.s.1
P = 0.0021
n.s.1
n.s.1
17/25 (76)
67/69 (97)
11/12 (92)
10/11 (91)
25/27 (93)
8/8 (100)
–
P < 0.0011
n.s.1
n.s.1
P = 0.0361
P < 0.0011
Krasnianski et al. (2006); bMeissner et al. (2005); BG, basal ganglia hyperintensities; P, statistical significance of frequency of each diagnostic test
compared with that in the MV2 subtype: 1Fisher exact test; 2chi-square test; n.s., not significant.
investigation showed the highest sensitivity among all surrogate CSF markers (89%) and can be regarded as useful in
the diagnosis of the MV2 subtype.
Prolonged disease duration, monosymptomatic disease
course for at least 6 months in some patients, late and relatively rare occurrence of myoclonus, and absence of PSWCs
may be responsible for the late sCJD diagnosis in MV2
patients. Sporadic CJD was initially proposed in none of
the MV2 patients in this study and was suspected for the
first time 8 months after the disease onset.
The MRI was the most useful diagnostic test in our
patients. In line with a previous study, the sensitivity of
MRI for basal ganglia hyperintensities in MV2 patients
was very high (90% for T2- and 100% for DWI-, FLAIRand PD-weighted scans) (Meissner et al., 2004). Only limited
data on MRI changes of the thalamus in sCJD have been
published so far (Collie et al., 2001). No thalamic hyperintensities could be detected in any scan of our MM1 control
group. Hyperintensities of the pulvinar were detected in 7 of
our 10 patients with FLAIR imaging (70%) and in 7 of
8 patients with available DWI (88%). In comparison, a previous study on different CJD subtypes, which included only
one patient with a known MV genotype (prion protein type
was not defined), detected thalamic hyperintensities on DWI
in 12.5% of patients investigated (Shiga et al., 2004). These
changes were also observed in a further study in 34% on
FLAIR and DWI (Young et al., 2005). However, the sCJD
subtype was not reported. Therefore, it could be speculated
that these findings may be due to a high proportion of MV2
patients (Young et al., 2005). While one patient showed a
classical pulvinar sign as found in 78% of vCJD patients,
thalamic hyperintensities in other patients were clearly visible but not more prominent than those in basal ganglia
(Collie et al., 2001). Additionally, hyperintense dorsomedial
thalamic nuclei could be found in three out of four of our
patients with a positive PD-weighted MRI (Fig. 1) resembling the ‘hockey stick sign’ described in vCJD patients
(Zeidler et al., 2000). A classical pulvinar sign was reported
in a patient with the VV1 subtype (Zeidler et al., 2000), and
pulvinar hyperintensities less prominent than in basal ganglia
were observed in a further VV1 and two MV2 patients (Haik
et al., 2002; Martindale et al., 2003; Rossetti et al., 2003;
Petzold et al., 2004). Such a high frequency of distinct thalamic hyperintensities (up to 88% on DWI in our patients)
has not been reported for any sCJD subtype including
previous studies on the MV2 subtype (Zerr et al., 2000b;
Meissner et al., 2004).
Compared with results of diagnostic tests in other sCJD
subtypes included in the German CJD Surveillance Study,
the lowest 14-3-3 protein sensitivity, but the highest MRI
sensitivity was obtained in the MV2 subtype. The EEG had a
high diagnostic value only in the MM1/MV1 subtype
(Table 9).
The codon 129 polymorphism was shown to influence the
sensitivity of diagnostic tests in sCJD. The prevalence of
PSWCs in EEG was significantly lower in MV and VV
CJD patients (Zerr et al., 2000b). Heterozygotes had also a
significantly lower 14-3-3 protein sensitivity (Zerr et al.,
2000b; Castellani et al., 2004). In contrast, the likelihood
of a positive MR scan was higher in MV patients, but
also in those with VV genotype (Meissner et al., 2004).
Codon 129 heterozygosity as well as the prion protein
type 2 were found to be associated with longer disease duration (Pocchiari et al., 2004). No clear influence of the prion
protein type on MRI sensitivity was reported so far, although
slight tendency towards higher MRI sensitivity seems to exist
in patients with the prion protein type 2. EEG and protein
14-3-3 sensitivity was higher in the prion protein type 1
(Zerr et al., 2000b; Castellani et al., 2004). These findings
correspond to the results obtained in the MV2 patients
included in this study.
About 25% of our MV2 patients could be classified either
as possible sCJD or as possible vCJD and one patient as
probable vCJD or probable sCJD according to WHO criteria
(WHO, 1998, 2001; Will et al., 2000). This particular patient
presented with progressive neuropsychiatric disorder of
more than 6 months duration (8 months). He showed
such early psychiatric symptoms as delusions and social
withdrawal as well as ataxia, myoclonus and dementia
required by WHO criteria for vCJD. The patient also had
no PSWCs in EEG, and bilateral pulvinar sign on MRI was
detected. Although the patient fulfilled WHO criteria for
probable vCJD, he developed ataxia and dementia as early
as 2 months after symptom onset, did not show any sensory
symptoms and was 62 years old. The 14-3-3 test was
positive. These facts suggested the diagnosis of probable
sCJD, rather than of probable vCJD, but did not contradict
vCJD criteria.
The MV2 subtype of sCJD
Histological changes were predominantly found in the
thalamus, basal ganglia and limbic cortex. In addition to a
significant correlation between disease duration and cortical
involvement also reported in the previous study (Parchi et al.,
1999), a significant correlation between disease duration and
nerve cell loss was found in the pulvinar in our MV2 patients.
A high degree of gliosis in the pulvinar supports the hypothesis of gliosis as the pathological correlate of the high thalamic
signal intensity (Collie et al., 2003). According to a previous
study, the MM1 subtype not associated with the pulvinar sign
shows a lower thalamic gliosis rate (Parchi et al., 1999).
Although the vermis in MV2 patients in the present and
previous studies showed relatively mild pathological changes,
severe gait and trunk ataxia was one of the most prominent
clinical features (Parchi et al., 1999; Zerr et al., 2000b). Pronounced pathology of the frontal cortex suggested an impairment of the frontopontocerebellar tract as one of the possible
explanations for the severe ataxia in the MV2 subtype (Terry
and Rosenberg, 1995). Consistent with previous studies, kuru
plaques were found in all patients (Parchi et al., 1999; Zerr
et al., 2000b). These changes are also found in kuru, a prion
disease transmitted by cannibalism in New Guinea, and are
reminiscent of the ‘florid plaques’ typically detected in vCJD
(Gajdusek and Zigas, 1957; Will et al., 1996). However, the
reasons for such changes in the MV2 subtype of sCJD are
unknown.
Conclusion
At least one of the three diagnostic tests, i.e. MRI, tau and
14-3-3 protein studies, was positive in all patients investigated and supported the clinical sCJD diagnosis. The MRI
was very sensitive in MV2 patients, and thalamic hyperintensities were observed significantly more frequently than
in typical sCJD. Prolonged disease duration, early and prominent psychiatric symptoms, lack of PSWCs, thalamic
hyperintensities on MRI and rather low 14-3-3 protein
sensitivity in the MV2 subtype delay the sCJD diagnosis
and may be suspicious for vCJD. Many features of the
MV2 subtype seem to be more similar to those of vCJD
than sCJD. However, distinct sensory symptoms and
young age at onset are not common in the MV2 subtype,
and the classical pulvinar sign frequently found in vCJD was
detected in only one of our MV2 patients.
Acknowledgements
The authors thank Ms Bodemer, Ms Ciesielczyk, Ms Henn
and Ms Staniszewski for technical assistance. The assistance
of Ms Zellner and Ms Schneider-Dominco is gratefully
acknowledged. The authors thank Dr R. G. Will (Edinburgh)
for his helpful comments on the manuscript. This study was
supported by grants from the Federal Ministry of Health and
Social Security (325-4471-02/15), the European Commission
(QLG3-CT-2002-81606), and the Federal Ministry of
Education and Research (01GI0301).
Brain (2006), 129, 2288–2296
2295
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